Inhibitors of bruton&#39;s tyrosine kinase

ABSTRACT

Described herein are kinase inhibitor compounds, methods for synthesizing such inhibitors, and methods for using such inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate inhibitor of a protein, including a kinase.

CROSS-REFERENCE

This application claims the benefit of U.S. provisional application Ser.No. 61/647,956, filed May 16, 2012, which is incorporated by referencein its entirety.

FIELD OF THE INVENTION

Described herein are kinase inhibitor compounds, methods forsynthesizing such inhibitors, and methods for using such inhibitors inthe treatment of diseases.

BACKGROUND OF THE INVENTION

A kinase, alternatively known as a phosphotransferase, is a type ofenzyme that transfers phosphate groups from high-energy donor molecules,such as ATP, to specific target molecules; the process is termedphosphorylation. Protein kinases, which act on and modify the activityof specific proteins, are used to transmit signals and control complexprocesses in cells. Up to 518 different kinases have been identified inhumans. Their enormous diversity and role in signaling makes themattractive targets for drug design.

SUMMARY OF THE INVENTION

Described herein are inhibitors of Bruton's tyrosine kinase (Btk). Alsodescribed herein are methods for synthesizing such inhibitors, methodsfor using such inhibitors in the treatment of diseases (includingdiseases wherein inhibition of Btk provides therapeutic benefit to apatient having the disease). Further described are pharmaceuticalformulations that include an inhibitor of Btk.

In one aspect, provided herein are compounds of Formula (I) having thestructure:

wherein:

-   -   R_(a), R_(b), R_(c), R_(d) and R_(e) are each independently        selected from H, F, Cl, Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and        —CO₂R₃; or    -   R_(a) or R_(b) together with one of R_(e), R_(d) and R_(e) and        the carbon atoms to which they are attached form an epoxide;        wherein R_(a), R_(b), R_(c), R_(d), and R_(e) cannot all be H;    -   X is F, Cl, Br, I, or CF₃;    -   Y is F, Cl, Br, or I; or —OC₁-C₂alkyl optionally substituted        with halogen or —OC₁-C₂alkyl; or an optionally substituted        C₂-C₅heterocycle;    -   R₂ is selected from H, C₁-C₄alkyl, a cysteine amino acid        fragment, and a glutathione fragment;    -   each R₃ is independently selected from H, C₁-C₄alkyl, phenyl,        and benzyl; or a pharmaceutically acceptable salt or solvate        thereof.

In one embodiment is a compound of Formula (I) wherein R_(a) is H. Inanother embodiment is a compound of Formula (I) wherein R_(b) is —OR₃.In yet another embodiment is a compound of Formula (I) wherein R₃ is H.In a further embodiment is a compound of Formula (I) wherein at leasttwo of R_(c), R_(d), and R_(e) is H. In yet a further embodiment is acompound of Formula (I) wherein R_(c) and R_(d) are both H. In oneembodiment is a compound of Formula (I) wherein R_(e) is —OR₃. Inanother embodiment is a compound of Formula (I) wherein R₃ is H. Inanother embodiment is a compound of Formula (I) wherein R_(a) and R_(b)are both H. In yet another embodiment is a compound of Formula (I)wherein R_(a) is H and R_(b) is —OR₃. In a further embodiment is acompound of Formula (I) wherein R₃ is H. In yet a further embodiment isa compound of Formula (I) wherein R_(c), R_(d), and R_(e) are eachindependently H. In one embodiment is a compound of Formula (I) whereinR_(a) is H and R_(b) is —OR₃. In another embodiment is a compound ofFormula (I) wherein R₃ is H. In yet another embodiment is a compound ofFormula (I) wherein R_(a) or R_(b) together with one of R_(c), R_(d) andR_(e) and the carbon atoms to which they are attached form an epoxide.

In another aspect, provided herein are compounds of Formula (II) havingthe structure:

wherein:

R_(a), R_(b), R_(e), R_(d) and R_(e) are each independently selectedfrom H, F, Cl, Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and —CO₂R₃; or

R_(a) or R_(b) together with one of R_(c), R_(d) and R_(e) and thecarbon atoms to which they are attached form an epoxide; wherein R_(a),R_(b), R_(c), R_(d), and R_(e) cannot all be H;

R₂ is selected from H, C₁-C₄alkyl, a cysteine amino acid fragment, and aglutathione fragment;

each R₃ is independently selected from H, C₁-C₄alkyl, phenyl, andbenzyl; or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment is a compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.

In one aspect is a pharmaceutical composition comprising a compoundhaving the structure of Formula (I):

wherein:

-   -   R_(a), R_(b), R_(c), R_(d) and R_(e) are each independently        selected from H, F, Cl, Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and        —CO₂R₃; or    -   R_(a) or R_(b) together with one of R_(c), R_(d) and R_(e) and        the carbon atoms to which they are attached form an epoxide;        wherein R_(a), R_(b), R_(c), R_(d), and R_(e) cannot all be H;    -   X is F, Cl, Br, I, or CF₃;    -   Y is F, Cl, Br, or I; or —OC₁-C₂alkyl optionally substituted        with halogen or —OC₁-C₂alkyl; or an optionally substituted        C₂-C₅heterocycle;    -   R₂ is selected from H, C₁-C₄alkyl, a cysteine amino acid        fragment, and a glutathione fragment;    -   each R₃ is independently selected from H, C₁-C₄alkyl, phenyl,        and benzyl; or a pharmaceutically acceptable salt or solvate        thereof; and a pharmaceutically acceptable excipient, binder or        carrier.

In certain embodiments, provided herein is a pharmaceutical compositioncontaining: i) a physiologically acceptable carrier, diluent, and/orexcipient; and ii) one or more compounds provided herein.

In certain embodiments, the compound of Formula (I) is in an isolatedform.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only. The section headingsused herein are for organizational purposes only and are not to beconstrued as limiting the subject matter described.

DETAILED DESCRIPTION OF THE INVENTION Certain Terminology

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

Definition of standard chemistry terms are found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, proteinchemistry, biochemistry, recombinant DNA techniques and pharmacology,within the skill of the art are employed. Unless specific definitionsare provided, the nomenclature employed in connection with, and thelaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry describedherein are those known in the art. Standard techniques are optionallyused for chemical syntheses, chemical analyses, pharmaceuticalpreparation, formulation, and delivery, and treatment of patients.Standard techniques are optionally used for recombinant DNA,oligonucleotide synthesis, and tissue culture and transformation (e.g.,electroporation, lipofection). Reactions and purification techniques areperformed using documented methodologies or as described herein.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such optionallyvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to limit the scope of the methods and compositions describedherein, which will be limited only by the appended claims.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety includes a “saturated alkyl” group, which means that it does notcontain any alkene or alkyne moieties. The alkyl moiety also includes an“unsaturated alkyl” moiety, which means that it contains at least onealkene or alkyne moiety. An “alkene” moiety refers to a group that hasat least one carbon-carbon double bond, and an “alkyne” moiety refers toa group that has at least one carbon-carbon triple bond. The alkylmoiety, whether saturated or unsaturated, includes branched, straightchain, or cyclic moieties. Depending on the structure, an alkyl groupincludes a monoradical or a diradical (i.e., an alkylene group), and ifa “lower alkyl” having 1 to 6 carbon atoms.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

The “alkyl” moiety optionally has 1 to 10 carbon atoms (whenever itappears herein, a numerical range such as “1 to 10” refers to eachinteger in the given range; e.g., “1 to 10 carbon atoms” means that thealkyl group is selected from a moiety having 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms,although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated). The alkyl group of thecompounds described herein may be designated as “C₁-C₄ alkyl” or similardesignations. By way of example only, “C₁-C₄ alkyl” indicates that thereare one to four carbon atoms in the alkyl chain, i.e., the alkyl chainis selected from among methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, and t-butyl. Thus C₁-C₄ alkyl includes C₁-C₂ alkyland C₁-C₃ alkyl. Alkyl groups are optionally substituted orunsubstituted. Typical alkyl groups include, but are in no way limitedto, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

“Alkoxyalkyl” refers to an alkyl radical, as defined herein, substitutedwith an alkoxy group, as defined herein.

The term “amino acid fragment” refers to a portion of an amino acid,such as by way of example only, the 20 common, genetically-encoded aminoacids (i.e., alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine, and valine), or a dipeptide, tripeptide or otherpolypeptide comprising a combination of the 20 common amino acids or anon-natural amino acid. In some embodiments, the amino acid fragment isattached to the compound of Formula (I) via the side chain of the aminoacid. In one embodiment, the amino acid fragment is a cysteine fragmentwherein the remaining portion of the compound of Formula (I) is boundvia a sulfur bond. In another embodiment, the amino acid fragment is aglutathione fragment wherein the remaining portion of a compound ofFormula (I) is bound via a sulfur bond of the glutathione fragment. Inanother embodiment, the amino acid fragments are derived from beta-aminoacids. In further embodiments, the amino acid fragments are derived fromportions of polypeptides or proteins. In yet further embodiments, theamino acid fragment is attached to the compound of Formula (I) via theN-terminal or the acyl-terminal of the amino acid.

The term “ester” refers to a chemical moiety with formula —COOR₃, whereR₃ is selected from among C₁-C₄alkyl, phenyl or benzyl. Any hydroxy, orcarboxyl side chain on the compounds described herein can be esterified.The procedures and specific groups to make such esters are found insources such as Greene and Wuts, Protective Groups in Organic Synthesis,3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, which isincorporated herein by reference for this disclosure.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl,fluorenyl, and indenyl. Depending on the structure, an aryl group can bea monoradical or a diradical (i.e., an arylene group).

The term “carbonyl” as used herein refers to a group containing a moietyselected from the group consisting of —C(O)—, —S(O)—, —S(O)2-, and—C(S)—, including, but not limited to, groups containing a least oneketone group, and/or at least one aldehyde group, and/or at least oneester group, and/or at least one carboxylic acid group, and/or at leastone thioester group. Such carbonyl groups include ketones, aldehydes,carboxylic acids, esters, and thioesters. In some embodiments, suchgroups are a part of linear, branched, or cyclic molecules.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo and iodo.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms are typically independently selected from among oxygen,sulfur, nitrogen, silicon and phosphorus, but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can all be the same as one another, or some orall of the two or more heteroatoms can each be different from theothers.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

A “thioalkoxy” or “alkylthio” group refers to a —S-alkyl group.

A “SH” group is also referred to either as a thiol group or a sulfhydrylgroup.

The term “acceptable” or “pharmaceutically acceptable”, with respect toa formulation, composition or ingredient, as used herein, means havingno persistent detrimental effect on the general health of the subjectbeing treated or does not abrogate the biological activity or propertiesof the compound, and is relatively nontoxic.

As used herein, the term “agonist” refers to a compound, the presence ofwhich results in a biological activity of a protein that is the same asthe biological activity resulting from the presence of a naturallyoccurring ligand for the protein, such as, for example, Btk.

As used herein, the term “partial agonist” refers to a compound thepresence of which results in a biological activity of a protein that isof the same type as that resulting from the presence of a naturallyoccurring ligand for the protein, but of a lower magnitude.

As used herein, the term “antagonist” refers to a compound, the presenceof which results in a decrease in the magnitude of a biological activityof a protein. In certain embodiments, the presence of an antagonistresults in complete inhibition of a biological activity of a protein,such as, for example, Btk. In certain embodiments, an antagonist is aninhibitor.

As used herein, “amelioration” of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

“Bioavailability” refers to the percentage of the weight of compoundsdisclosed herein, such as, compounds of Formula (I) or Formula (II),dosed that is delivered into the general circulation of the animal orhuman being studied. The total exposure (AUC_((0-∞))) of a drug whenadministered intravenously is usually defined as 100% bioavailable (F%). “Oral bioavailability” refers to the extent to which compoundsdisclosed herein, such as, compounds of Formula (I) or Formula (II), areabsorbed into the general circulation when the pharmaceuticalcomposition is taken orally as compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of compoundsdisclosed herein, such as, compounds of Formula (I) or Formula (II), inthe plasma component of blood of a subject. It is understood that theplasma concentration of compounds of Formula (I) or Formula (II), mayvary significantly between subjects, due to variability with respect tometabolism and/or possible interactions with other therapeutic agents.In accordance with one embodiment disclosed herein, the blood plasmaconcentration of the compounds of Formula (I) or Formula (II), does varyfrom subject to subject. Likewise, values such as maximum plasmaconcentration (C_(max)) or time to reach maximum plasma concentration(T_(max)), or total area under the plasma concentration time curve(AUC_((0-∞))) may vary from subject to subject. Due to this variability,the amount necessary to constitute “a therapeutically effective amount”of a compound of Formula (I) or Formula (II) is expected to vary fromsubject to subject.

The term “Bruton's tyrosine kinase,” as used herein, refers to Bruton'styrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Pat. No.6,326,469 (GenBank Accession No. NP_(—)000052).

The term “Bruton's tyrosine kinase homolog,” as used herein, refers toorthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse(GenBank Accession No. AAB47246), dog (GenBank Accession No.XP_(—)549139.), rat (GenBank Accession No. NP_(—)001007799), chicken(GenBank Accession No. NP_(—)989564), or zebra fish (GenBank AccessionNo. XP_(—)698117), and fusion proteins of any of the foregoing thatexhibit kinase activity towards one or more substrates of Bruton'styrosine kinase (e.g. a peptide substrate having the amino acid sequence“AVLESEEELYSSARQ”).

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition including a compound as disclosed herein required to providea clinically significant decrease in disease symptoms without undueadverse side effects. An appropriate “effective amount” in anyindividual case is optionally determined using techniques, such as adose escalation study. The term “therapeutically effective amount”includes, for example, a prophylactically effective amount. An“effective amount” of a compound disclosed herein is an amount effectiveto achieve a desired pharmacologic effect or therapeutic improvementwithout undue adverse side effects. It is understood that “an effectamount” or “a therapeutically effective amount” can vary from subject tosubject, due to variation in metabolism of the compound of Formula (I)or Formula (II), age, weight, general condition of the subject, thecondition being treated, the severity of the condition being treated,and the judgment of the prescribing physician.

The terms “enhance” or “enhancing” means to increase or prolong eitherin potency or duration a desired effect. By way of example, “enhancing”the effect of therapeutic agents refers to the ability to increase orprolong, either in potency or duration, the effect of therapeutic agentson during treatment of a disease, disorder or condition. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of a therapeutic agent in the treatmentof a disease, disorder or condition. When used in a patient, amountseffective for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

The term “homologous cysteine,” as used herein refers to a cysteineresidue found with in a sequence position that is homologous to that ofcysteine 481 of Bruton's tyrosine kinase, as defined herein. Forexample, cysteine 482 is the homologous cysteine of the rat ortholog ofBruton's tyrosine kinase; cysteine 479 is the homologous cysteine of thechicken ortholog; and cysteine 481 is the homologous cysteine in thezebra fish ortholog. In another example, the homologous cysteine of TXK,a Tec kinase family member related to Bruton's tyrosine, is Cys 350. Seealso the sequence alignments of tyrosine kinases (TK) published on theworld wide web at kinase.com/human/kinome/phylogeny.html.

The terms “inhibits”, “inhibiting”, or “inhibitor” of a kinase, as usedherein, refer to inhibition of enzymatic phosphotransferase activity.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

The term “plasma half life,” as used herein refers to half-life in rat,dog or human as determined by measure drug concentration over time inplasma following a single dose and fitting data to standardpharmacokinetic models using software such as WinNonLin to determine thetime at which drug has been 50% eliminated from plasma.

The term “prophylactically effective amount,” as used herein, refersthat amount of a composition applied to a patient which will relieve tosome extent one or more of the symptoms of a disease, condition ordisorder being treated. In such prophylactic applications, such amountsmay depend on the patient's state of health, weight, and the like.

As used herein, the term “selective binding compound” refers to acompound that selectively binds to any portion of one or more targetproteins.

As used herein, the term “selectively binds” refers to the ability of aselective binding compound to bind to a target protein, such as, forexample, Btk, with greater affinity than it binds to a non-targetprotein. In certain embodiments, specific binding refers to binding to atarget with an affinity that is at least about 10, about 50, about 100,about 250, about 500, about 1000 or more times greater than the affinityfor a non-target.

As used herein, the term “selective modulator” refers to a compound thatselectively modulates a target activity relative to a non-targetactivity. In certain embodiments, specific modulator refers tomodulating a target activity at least about 10, about 50, about 100,about 250, about 500, about 1000 times more than a non-target activity.

The term “substantially purified,” as used herein, refers to a componentof interest that may be substantially or essentially free of othercomponents which normally accompany or interact with the component ofinterest prior to purification. By way of example only, a component ofinterest may be “substantially purified” when the preparation of thecomponent of interest contains less than about 30%, less than about 25%,less than about 20%, less than about 15%, less than about 10%, less thanabout 5%, less than about 4%, less than about 3%, less than about 2%, orless than about 1% (by dry weight) of contaminating components. Thus, a“substantially purified” component of interest may have a purity levelof about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,about 96%, about 97%, about 98%, about 99% or greater.

The term “subject” as used herein, refers to an animal which is theobject of treatment, observation or experiment. By way of example only,a subject may be, but is not limited to, a mammal including, but notlimited to, a human.

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a selective modulator. Certainexemplary target activities include, but are not limited to, bindingaffinity, signal transduction, enzymatic activity, tumor growth,inflammation or inflammation-related processes, and amelioration of oneor more symptoms associated with a disease or condition.

As used herein, the term “target protein” refers to a molecule or aportion of a protein capable of being bound by a selective bindingcompound. In certain embodiments, a target protein is Btk.

The terms “treat,” “treating” or “treatment”, as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition. The terms “treat,”“treating” or “treatment”, include, but are not limited to, prophylacticand/or therapeutic treatments.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as inhibition of Btk, in an assay that measures suchresponse.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

Inhibitor Compounds

In the following description of kinase inhibitor compounds suitable foruse in the methods described herein. Unless specific definitions areprovided, the nomenclature employed in connection with, and thelaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry describedherein are those known in the art. Standard techniques can be used forchemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients.

In one aspect, provided herein are compounds of Formula (I) having thestructure:

wherein:

-   -   R_(a), R_(b), R_(e), R_(d) and R_(e) are each independently        selected from H, F, Cl, Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and        —CO₂R₃; or    -   R_(a) or R_(b) together with one of R_(c), R_(d) and R_(e) and        the carbon atoms to which they are attached form an epoxide;        wherein R_(a), R_(b), R_(e), R_(d), and R_(e) cannot all be H;    -   X is F, Cl, Br, I, or CF₃;    -   Y is F, Cl, Br, or I; or —OC₁-C₂alkyl optionally substituted        with halogen or —OC₁-C₂alkyl; or an optionally substituted        C₂-C₅heterocycle;    -   R₂ is selected from H, C₁-C₄alkyl, a cysteine amino acid        fragment, and a glutathione fragment;    -   each R₃ is independently selected from H, C₁-C₄alkyl, phenyl,        and benzyl; or a pharmaceutically acceptable salt or solvate        thereof.

In one embodiment is a compound of Formula (I) wherein X is F, Cl, Br,I, or CF₃. In some embodiments, X is F. In some embodiments, X is Cl. Insome embodiments, X is Br. In some embodiments, X is I. In someembodiments, X is CF₃. In another embodiment is a compound of Formula(I) wherein Y is F, Cl, Br, or I; or —OC₁-C₂alkyl optionally substitutedwith halogen or —OC₁-C₂alkyl; or an optionally substitutedC₂-C₅heterocycle. In some embodiments is a compound of Formula (I)wherein Y is F, Cl, Br, or I. In some embodiments, Y is F. In someembodiments, Y is Cl. In some embodiments, Y is Br. In some embodiments,Y is I. In other embodiments is a compound of Formula (I) wherein Y is—OC₁-C₂alkyl optionally substituted with halogen or —OC₁-C₂alkyl. Insome embodiments, Y is —OCH₃. In some embodiments, Y is —OCH₂CH₃. Insome embodiments, Y is —OCH₂CH₂OCH₃. In another embodiment is a compoundof Formula (I) wherein Y is an optionally substituted C₂-C₅heterocycle.In another embodiment is a compound of Formula (I) wherein X is F and Yis —OCH₃. In another embodiment is a compound of Formula (I) wherein Xis F and Y is —OCH₂CH₃. In another embodiment is a compound of Formula(I) wherein X is F and Y is —OCH₂CH₂OCH₃. In another embodiment is acompound of Formula (I) wherein X is Cl and Y is —OCH₃. In anotherembodiment is a compound of Formula (I) wherein X is Cl and Y is—OCH₂CH₃. In another embodiment is a compound of Formula (I) wherein Xis Cl and Y is —OCH₂CH₂OCH₃.

In another embodiment is a compound of Formula (I) wherein R_(a), R_(b),R_(c), R_(d) and R_(e) are each independently selected from H, F, Cl,Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and —CO₂R₃. In another embodiment is acompound of Formula (I) wherein R_(a) is H. In another embodiment is acompound of Formula (I) wherein R_(b) is —OR₃. In yet another embodimentis a compound of Formula (I) wherein R₃ is H. In a further embodiment isa compound of Formula (I) wherein at least two of R_(c), R_(d), andR_(e) is H. In yet a further embodiment is a compound of Formula (I)wherein R_(c) and R_(d) are both H. In one embodiment is a compound ofFormula (I) wherein R_(e) is —OR₃. In another embodiment is a compoundof Formula (I) wherein R₃ is H. In another embodiment is a compound ofFormula (I) wherein R_(a) and R_(b) are both H. In another embodiment isa compound of Formula (I) wherein R_(a), R_(b), R_(c), R_(d) are H andR_(e) is —SR₂. In another embodiment is a compound of Formula (I)wherein R_(a), R_(b), R_(c), R_(d) are H, R_(e) is —SR₂, and R₂ is acysteine amino acid fragment. In another embodiment is a compound ofFormula (I) wherein R_(a), R_(b), R_(c), R_(d) are H, R_(e) is —SR₂, andR₂ is a glutathione fragment. In another embodiment is a compound ofFormula (I) wherein R_(a) is H and R_(b) is —OR₃. In another embodimentis a compound of Formula (I) wherein R_(a) is H and R_(b) is —OH. In yeta further embodiment is a compound of Formula (I) wherein R_(c), R_(d),and R_(e) are each independently H. In one embodiment is a compound ofFormula (I) wherein R_(a) is H and R_(b) is —OR₃. In another embodimentis a compound of Formula (I) wherein R₃ is H. In another embodiment is acompound of Formula (I) wherein R_(a), R_(c), R_(d), and R_(e) are eachH and R_(b) is —OH. In another embodiment is a compound of Formula (I)wherein R_(a), R_(b), R_(c), and R_(d) are each H and R_(e) is —OH. Inanother embodiment is a compound of Formula (I) wherein R_(a), R_(c),R_(d) are each H and R_(b) and R_(e) are each —OH. In yet anotherembodiment is a compound of Formula (I) wherein R_(a) or R_(b) togetherwith one of R_(c), R_(d) and R_(e) and the carbon atoms to which theyare attached form an epoxide.

In one embodiment is a compound of Formula (I) having the structure:

In another aspect, provided herein are compounds of Formula (II) havingthe structure:

wherein:

R_(a), R_(b), R_(c), R_(d) and R_(e) are each independently selectedfrom H, F, Cl, Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and —CO₂R₃; or

R_(a) or R_(b) together with one of R_(c), R_(d) and R_(e) and thecarbon atoms to which they are attached form an epoxide; wherein R_(a),R_(b), R_(c), R_(d), and R_(e) cannot all be H;

R₂ is selected from H, C₁-C₄alkyl, a cysteine amino acid fragment, and aglutathione fragment;

each R₃ is independently selected from H, C₁-C₄alkyl, phenyl, andbenzyl;

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment is a compound of Formula (II) wherein R_(a),R_(b), R_(c), R_(d) and R_(e) are each independently selected from H, F,Cl, Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and —CO₂R₃. In another embodimentis a compound of Formula (II) wherein R_(a) is H. In another embodimentis a compound of Formula (II) wherein R_(b) is —OR₃. In yet anotherembodiment is a compound of Formula (II) wherein R₃ is H. In a furtherembodiment is a compound of Formula (II) wherein at least two of R_(c),R_(d), and R_(e) is H. In yet a further embodiment is a compound ofFormula (II) wherein R_(c) and R_(d) are both H. In one embodiment is acompound of Formula (II) wherein R_(e) is —OR₃. In another embodiment isa compound of Formula (II) wherein R₃ is H. In another embodiment is acompound of Formula (II) wherein R_(a) and R_(b) are both H. In anotherembodiment is a compound of Formula (II) wherein R_(a), R_(b), R_(c),R_(d) are H and R_(e) is —SR₂. In another embodiment is a compound ofFormula (II) wherein R_(a), R_(b), R_(c), R_(d) are H, R_(e) is —SR₂,and R₂ is a cysteine amino acid fragment. In another embodiment is acompound of Formula (II) wherein R_(a), R_(b), R_(c), R_(d) are H, R_(e)is —SR₂, and R₂ is a glutathione fragment. In another embodiment is acompound of Formula (II) wherein R_(a) is H and R_(b) is —OR₃. Inanother embodiment is a compound of Formula (II) wherein R_(a) is H andR_(b) is —OH. In yet a further embodiment is a compound of Formula (II)wherein R_(c), R_(d), and R_(e) are each independently H. In oneembodiment is a compound of Formula (II) wherein R_(a) is H and R_(b) is—OR₃. In another embodiment is a compound of Formula (II) wherein R₃ isH. In another embodiment is a compound of Formula (II) wherein R_(a),R_(e), R_(d), and R_(e) are each H and R_(b) is —OH. In anotherembodiment is a compound of Formula (II) wherein R_(a), R_(b), R_(c),and R_(d) are each H and R_(e) is —OH. In another embodiment is acompound of Formula (II) wherein R_(a), R_(e), R_(d) are each H andR_(b) and R_(e) are each —OH. In yet another embodiment is a compound ofFormula (II) wherein R_(a) or R_(b) together with one of R_(c), R_(d)and R_(e) and the carbon atoms to which they are attached form anepoxide.

In one aspect, provided herein is a compound selected from among:N-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenyl)-2,3-dihydroxypropanamide,N-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenyl)-3-hydroxypropanamide,N-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenyl)-2-hydroxypropanamide,N-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenyl)oxirane-2-carboxamide,and(S)-2-amino-5-((R)-1-(carboxymethylamino)-3-(3-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenylamino)-3-oxopropylthio)-1-oxopropan-2-ylamino)-5-oxopentanoicacid; or a pharmaceutically acceptable salt, solvate or tautomeric formthereof.

In some embodiments, the inhibitors described herein are used for themanufacture of a medicament for treating any of the foregoing conditions(e.g., autoimmune diseases, inflammatory diseases, allergy disorders,B-cell proliferative disorders, or thromboembolic disorders).

In some embodiments, the inhibitor compound used for the methodsdescribed herein inhibits a kinase activity with an in vitro IC₅₀ ofless than about 10 μM. (e.g., less than about 1 μM, less than about 0.5μM, less than about 0.4 μM, less than about 0.3 μM, less than about 0.1,less than about 0.08 μM, less than about 0.06 μM, less than about 0.05μM, less than about 0.04 μM, less than about 0.03 μM, less than about0.02 μM, less than about 0.01, less than about 0.008 μM, less than about0.006 μM, less than about 0.005 μM, less than about 0.004 μM, less thanabout 0.003 μM, less than about 0.002 μM, less than about 0.001, lessthan about 0.00099 μM, less than about 0.00098 μM, less than about0.00097 μM, less than about 0.00096 μM, less than about 0.00095 μM, lessthan about 0.00094 μM, less than about 0.00093 μM, less than about0.00092, or less than about 0.00090 μM).

In one embodiment, the inhibitor compound selectively inhibits anactivated form of its target tyrosine kinase (e.g., a phosphorylatedform of the tyrosine kinase). For example, activated Btk istransphosphorylated at tyrosine 551. Thus, in these embodiments the Btkinhibitor inhibits the target kinase in cells only once the targetkinase is activated by the signaling events.

Preparation of Compounds

Compounds of any of Formula (I) or Formula (II) are optionallysynthesized using standard synthetic techniques or using such methodsknown in combination with methods described herein. In additions,solvents, temperatures and other reaction conditions are presentedherein for illustration only, and not to limit the scope of the methodsand compositions described herein. As a further guide the followingsynthetic methods may also be utilized.

The reactions are optionally employed in a linear sequence to providethe compounds described herein or used to synthesize fragments which aresubsequently joined by the methods described herein and/or documentedelsewhere.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein can be modified using variouselectrophiles or nucleophiles to form new functional groups orsubstituents. Table 1 entitled “Examples of Covalent Linkages andPrecursors Thereof” lists selected examples of covalent linkages andprecursor functional groups which yield and can be used as guidancetoward the variety of electrophiles and nucleophiles combinationsavailable. Precursor functional groups are shown as electrophilic groupsand nucleophilic groups.

TABLE 1 Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes orketones Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkylamines alkyl halides amines/anilines Esters alkyl halides carboxylicacids Thioethers alkyl halides Thiols Ethers alkyl halidesalcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkylsulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenolsEsters Anhydrides alcohols/phenols Carboxamides Anhydridesamines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides carboxylic acids amines/anilines Esters carboxylic acidsAlcohols hydrazines Hydrazides carboxylic acids N-acylureas orAnhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylicacids Thioethers Epoxides Thiols Thioethers haloacetamides ThiolsAmmotriazines halotriazines amines/anilines Triazinyl ethershalotriazines alcohols/phenols Amidines imido esters amines/anilinesUreas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenolsThioureas isothiocyanates amines/anilines Thioethers Maleimides ThiolsPhosphite esters phosphoramidites Alcohols Silyl ethers silyl halidesAlcohols Alkyl amines sulfonate esters amines/anilines Thioetherssulfonate esters Thiols Esters sulfonate esters carboxylic acids Etherssulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilinesSulfonate esters sulfonyl halides phenols/alcohols Alkyl thiolα,β-unsaturated ester thiols Alkyl ethers α,β-unsaturated ester alcoholsAlkyl amines α,β-unsaturated ester amines Alkyl thiol Vinyl sulfonethiols Alkyl ethers Vinyl sulfone alcohols Alkyl amines Vinyl sulfoneamines Vinyl sulfide Propargyl amide thiol

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, to avoid theirunwanted participation in the reactions. Protecting groups are used toblock some or all reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. In one embodiment, each protective group can be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval. Protective groups can be removed by acid, base, andhydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and may be used to protect carboxyand hydroxy reactive moieties in the presence of amino groups protectedwith Cbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties maybe blocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, or they may be blocked with oxidatively-removable protectivegroups such as 2,4-dimethoxybenzyl, while co-existing amino groups maybe blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure.

Synthesis of Compounds

In certain embodiments, provided herein are methods of making thetyrosine kinase inhibitor compounds described herein. In certainembodiments, compounds described herein are synthesized using thefollowing synthetic schemes. In other embodiments, compounds aresynthesized using methodologies analogous to those described below bythe use of appropriate alternative starting materials.

The starting material used for the synthesis of the compounds describedherein is either synthesized or obtained from commercial sources, suchas, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.), Bachem(Torrance, Calif.), or Sigma Chemical Co. (St. Louis, Mo.). Thecompounds described herein, and other related compounds having differentsubstituents are optionally synthesized using techniques and materials,such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY4^(th) Ed., Vols. A and B (Plenum 2000, 2001); Green and Wuts,PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999); Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991); and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). Other methods forthe synthesis of compounds described herein may be found inInternational Patent Publication No. WO 01/01982901, Arnold et al.Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat etal. Bioorganic & Medicinal Chemistry Letters 12 (2002) 1687-1690. As aguide the following synthetic methods may be utilized.

The products of the reactions are optionally isolated and purified, ifdesired, using conventional techniques, including, but not limited to,filtration, distillation, crystallization, chromatography and the like.Such materials are optionally characterized using conventional means,including physical constants and spectral data.

Compounds described herein are optionally prepared using the syntheticmethods described herein as a single isomer or a mixture of isomers.

A non-limiting example of a synthetic approach towards the preparationof a compound of Formula (I) is shown in Scheme I.

In one embodiment, 2,4-dichloro-5-fluoropyrimidine, t-butyl3-aminophenylcarbamate, and Hunig's base are heated at reflux in THF togive 1. Coupling of 1 and 4-(2-methoxyethoxy)aniline in the presence ofcatalytic acetic acid in t-amyl alcohol at reflux affords 2. Followingremoval of the Boc protecting group, the deprotected amine is acylatedwith acryloyl chloride to give 3. Dihydroxylation of 3 with osmiumtetroxide in t-BuOH affords diol 4.

The compounds prepared by the methods disclosed herein are purified byconventional means, such as, for example, filtration, recrystallization,chromatography, distillation, and combinations thereof.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

Further Forms of Compounds

Compounds disclosed herein have a structure of Formula (I) or Formula(II). It is understood that when reference is made to compoundsdescribed herein, it is meant to include compounds of any of Formula (I)or Formula (II), as well as to all of the specific compounds that fallwithin the scope of these generic formulae, unless otherwise indicated.

In some embodiments, the compounds described herein possess one or morestereocenters and in further embodiments, each center exists in the R orS configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. In other embodiments, stereoisomers areobtained, if desired, by methods such as, for example, the separation ofstereoisomers by chiral chromatographic columns.

In further embodiments, diastereomeric mixtures are separated into theirindividual diastereomers on the basis of their physical chemicaldifferences by methods known, for example, by chromatography and/orfractional crystallization. In one embodiment, enantiomers can beseparated by chiral chromatographic columns. In other embodiments,enantiomers can be separated by converting the enantiomeric mixture intoa diastereomeric mixture by reaction with an appropriate opticallyactive compound (e.g., alcohol), separating the diastereomers andconverting (e.g., hydrolyzing) the individual diastereomers to thecorresponding pure enantiomers. All such isomers, includingdiastereomers, enantiomers, and mixtures thereof are considered as partof the compositions described herein.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein. In somesituations, compounds exist as tautomers. All tautomers are includedwithin the scope of the compounds presented herein. In addition, thecompounds described herein can exist in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as water, ethanol,and the like. The solvated forms of the compounds presented herein arealso considered to be disclosed herein.

In some embodiments, compounds of Formula (I) or Formula (II) inunoxidized form are prepared from N-oxides of compounds of any ofFormula (I) or Formula (II) by treating with a reducing agent, such as,but not limited to, sulfur, sulfur dioxide, triphenyl phosphine, lithiumborohydride, sodium borohydride, phosphorus trichloride, tribromide, orthe like in a suitable inert organic solvent, such as, but not limitedto, acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 80° C.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulas and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as ²H,³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively. Certainisotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Further,substitution with isotopes such as deuterium, i.e., ²H, can affordcertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements.

In one embodiment is an isolated and/or pure form of a compound ofFormula (I) or Formula (II). In another embodiment, is a compound ofFormula (I) or Formula (II) wherein the compound is at least about 40%pure. In another embodiment, is a compound of Formula (I) or Formula(II) wherein the compound is at least about 50%, about 60%, about 70%,about 80%, about 90%, about 95% pure. In yet another embodiment is acompound of Formula (I) or Formula (II) in an isolated form. In yetanother embodiment, is a compound of Formula (I) or Formula (II) whereinthe compound is purified by chromatography.

Compounds described herein (for example, compounds of Formula (I) orFormula (II)) are optionally in the form of, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, andthe like; or with an organic acid such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; (2) salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium),an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion;or coordinates with an organic base. Acceptable organic bases includeethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. Acceptable inorganic bases includealuminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, and the like.

The corresponding counterions of the pharmaceutically acceptable saltsare optionally analyzed and identified using various methods including,but not limited to, ion exchange chromatography, ion chromatography,capillary electrophoresis, inductively coupled plasma, atomic absorptionspectroscopy, mass spectrometry, or any combination thereof.

The salts are recovered by using at least one of the followingtechniques: filtration, precipitation with a non-solvent followed byfiltration, evaporation of the solvent, or, in the case of aqueoussolutions, lyophilization.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and areoptionally formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. Solvates of compounds describedherein can be conveniently prepared or formed during the processesdescribed herein. In addition, the compounds provided herein can existin unsolvated as well as solvated forms. In general, the solvated formsare considered equivalent to the unsolvated forms for the purposes ofthe compounds and methods provided herein.

It should be understood that a reference to a salt includes the solventaddition forms or crystal forms thereof, particularly solvates orpolymorphs. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and are often formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Polymorphs includethe different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Various factors such as the recrystallization solvent,rate of crystallization, and storage temperature may cause a singlecrystal form to dominate.

Compounds described herein are optionally in various forms, includingbut not limited to, amorphous forms, milled forms and nano-particulateforms. In addition, compounds described herein include crystallineforms, also known as polymorphs. Polymorphs include the differentcrystal packing arrangements of the same elemental composition of acompound. Polymorphs usually have different X-ray diffraction patterns,infrared spectra, melting points, density, hardness, crystal shape,optical and electrical properties, stability, and solubility. Variousfactors such as the recrystallization solvent, rate of crystallization,and storage temperature may cause a single crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UVIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Therapeutic Uses of Inhibitor Compounds

In one aspect, provided herein are methods for treating a patient byadministering a compound provided herein. In some embodiments, providedherein is a method of inhibiting the activity of tyrosine kinase(s),such as Btk, or of treating a disease, disorder, or condition, whichbenefit from inhibition of tyrosine kinase(s), such as Btk, in apatient, which includes administering to the patient a therapeuticallyeffective amount of at least one of any of the compounds describedherein, or pharmaceutically acceptable salt, pharmaceutically acceptabletautomer, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate.

In another aspect, provided herein is the use of a compound disclosedherein for inhibiting Bruton's tyrosine kinase (Btk) activity or for thetreatment of a disease, disorder, or condition, which benefit frominhibition of Bruton's tyrosine kinase (Btk) activity.

In some embodiments, compounds provided herein are administered to ahuman. In some embodiments, compounds provided herein are orallyadministered. In other embodiments, the pharmaceutical formulation thatis formulated for a route of administration is selected from oraladministration, parenteral administration, buccal administration, nasaladministration, topical administration, or rectal administration.

In other embodiments, compounds provided herein are used for theformulation of a medicament for the inhibition of tyrosine kinaseactivity. In some other embodiments, compounds provided herein are usedfor the formulation of a medicament for the inhibition of Bruton'styrosine kinase (Btk) activity.

In a further aspect, provided herein is a method for treating anautoimmune disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (I) or Formula (II). In oneembodiment, the autoimmune disease is arthritis. In another embodiment,the autoimmune disease is lupus. In some embodiments, the autoimmunedisease is inflammatory bowel disease (including Crohn's disease andulcerative colitis), rheumatoid arthritis, psoriatic arthritis,osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes,myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome,acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, orvulvodynia.

In a further aspect, provided herein is a method for treating aheteroimmune condition or disease by administering to a subject in needthereof a composition containing a therapeutically effective amount ofat least one compound having the structure of Formula (I) or Formula(II). In some embodiments, the heteroimmune condition or disease isgraft versus host disease, transplantation, transfusion, anaphylaxis,allergy, type I hypersensitivity, allergic conjunctivitis, allergicrhinitis, or atopic dermatitis.

In a further aspect, provided herein is a method for treating aninflammatory disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (I) or Formula (II). Insome embodiments, the inflammatory disease is asthma, inflammatory boweldisease (including Crohn's disease and ulcerative colitis),appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis,cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis,cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis,endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis,myelitis myocarditis, myositis, nephritis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis,pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis,vasculitis, or vulvitis.

In yet another aspect, provided herein is a method for treating a cancerby administering to a subject in need thereof a composition containing atherapeutically effective amount of at least one compound having thestructure of Formula (I) or Formula (II). In one embodiment, the canceris a B-cell proliferative disorder, e.g., diffuse large B cell lymphoma,follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocyticleukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma/Waldenström macroglobulinemia, splenic marginal zone lymphoma,plasma cell myeloma, plasmacytoma, extranodal marginal zone B celllymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma,mediastinal (thymic) large B cell lymphoma, intravascular large B celllymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, orlymphomatoid granulomatosis. In some embodiments, where the subject issuffering from a cancer, an anti-cancer agent is administered to thesubject in addition to one of the above-mentioned compounds. In oneembodiment, the anti-cancer agent is an inhibitor of mitogen-activatedprotein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901,ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002.

In another aspect, provided herein is a method for treating athromboembolic disorder by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (I) or Formula (II). Insome embodiments, the thromboembolic disorder is myocardial infarct,angina pectoris, reocclusion after angioplasty, restenosis afterangioplasty, reocclusion after aortocoronary bypass, restenosis afteraortocoronary bypass, stroke, transitory ischemia, a peripheral arterialocclusive disorder, pulmonary embolism, or deep venous thrombosis.

In another aspect, provided herein is a method for treating amastocytosis by administering to a subject in need thereof a compositioncontaining a therapeutically effective amount of at least one compoundhaving the structure of Formula (I) or Formula (II).

In yet another aspect, provided herein is a method for treating anosteoporosis or bone resorption disorders by administering to a subjectin need thereof a composition containing a therapeutically effectiveamount of at least one compound having the structure of Formula (I) orFormula (II).

Also described herein are kinase inhibitors that selectively bind to aprotein tyrosine kinase selected from Btk, a Btk homolog, and a Btkkinase cysteine homolog, in which the kinase inhibitor reversibly andnon-selectively binds to a multiplicity of protein tyrosine kinases. Inone embodiment the plasma half life of the kinase inhibitor is less thanabout 4 hours. In another embodiment the plasma half life of the kinaseinhibitor is less than about 3 hours.

In a further embodiment are kinase inhibitors that selectively bind toat least one of Btk, Jak3, Blk, Bmx, Tec, and Itk. In another embodimentare kinase inhibitors that selectively bind to Btk. In anotherembodiment are kinase inhibitors that selectively bind to Jak3. Inanother embodiment are kinase inhibitors that selectively bind to Tec.In another embodiment are kinase inhibitors that selectively bind toItk. In another embodiment are kinase inhibitors that selectively bindto Btk and Tec. In another embodiment are kinase inhibitors thatselectively bind to Blk. In yet a further embodiment are kinaseinhibitors that reversibly and non-selectively bind to a multiplicity ofsrc-family protein kinase inhibitors.

Also described herein are inhibitors that are identified using suchmethods, assays and systems. In some embodiments, the inhibitor is aselective inhibitor, including selectivity for a particular Btk kinasecysteine homolog over other Btk kinase cysteine homologs.

Further described herein are pharmaceutical formulations comprising thekinase inhibitors of any kinase inhibitor compound previously listed. Inone embodiment the pharmaceutical formulation includes a pharmaceuticalacceptable excipient. In some embodiments, pharmaceutical formulationsprovided herein are administered to a human. In some embodiments, theselective kinase inhibitors provided herein are orally administered. Inother embodiments, the selective kinase inhibitors provided herein areused for the formulation of a medicament for the inhibition of tyrosinekinase activity. In some other embodiments, the selective kinaseinhibitors provided herein are used for the formulation of a medicamentfor the inhibition of a kinase activity, including a tyrosine kinaseactivity, including a Btk activity, including a Btk homolog activity,including a Btk kinase cysteine homolog activity.

In any of the aforementioned aspects are further embodiments in whichadministration is enteral, parenteral, or both, and wherein (a) theeffective amount of the compound is systemically administered to themammal; (b) the effective amount of the compound is administered orallyto the mammal; (c) the effective amount of the compound is intravenouslyadministered to the mammal; (d) the effective amount of the compoundadministered by inhalation; (e) the effective amount of the compound isadministered by nasal administration; or (f) the effective amount of thecompound is administered by injection to the mammal; (g) the effectiveamount of the compound is administered topically (dermal) to the mammal;(h) the effective amount of the compound is administered by ophthalmicadministration; or (i) the effective amount of the compound isadministered rectally to the mammal. In further embodiments thepharmaceutical formulation is formulated for a route of administrationselected from oral administration, parenteral administration, buccaladministration, nasal administration, topical administration, or rectaladministration.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the pharmaceuticalformulation, including further embodiments in which (i) thepharmaceutical formulations is administered once; (ii) thepharmaceutical formulations is administered to the mammal once a day;(iii) the pharmaceutical formulations is administered to the mammalmultiple times over the span of one day; (iv) continually; or (v)continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the pharmaceuticalformulations, including further embodiments in which (i) thepharmaceutical formulations is administered in a single dose; (ii) thetime between multiple administrations is every 6 hours; (iii) thepharmaceutical formulations is administered to the mammal every 8 hours.In further or alternative embodiments, the method comprises a drugholiday, wherein the administration of the pharmaceutical formulationsis temporarily suspended or the dose of the pharmaceutical formulationsbeing administered is temporarily reduced; at the end of the drugholiday, dosing of the pharmaceutical formulations is resumed. Thelength of the drug holiday varies from 2 days to 1 year.

In some aspects described herein the inhibitor is selective for onekinase selected from Btk, a Btk homolog, and a Btk kinase cysteinehomolog over at least one other kinase selected from Btk, a Btk homolog,and a Btk kinase cysteine homolog. In other aspects described herein theinhibitor is selective for at least one kinase selected from Btk, a Btkhomolog, and a Btk kinase cysteine homolog over at least one othernon-kinase molecule having an accessible SH group.

Described herein are methods, compositions, uses and medicaments for thetreatment of disorders comprising administering to a patient in need aninhibitor of an ACK. In some embodiments, the ACK is Btk or a Btkhomolog. In further embodiments, the ACK is Blk or a Blk homolog. In yetfurther embodiments, the ACK is tyrosine kinases that share homologywith Btk by having a cysteine residue (including a Cys 481 residue) thatcan form a bond with the inhibitor.

The methods described herein (which includes uses of a pharmaceuticalcomposition to treat a disease or disorder, or uses of a compound toform a medicament for treating a disease or disorder) includeadministering to a subject in need a composition containing atherapeutically effective amount of one or more Btk inhibitor compoundsdescribed herein. Without being bound by theory, the diverse rolesplayed by Btk signaling in various hematopoietic cell functions, e.g.,B-cell receptor activation, show that small molecule Btk inhibitors areuseful for reducing the risk of or treating a variety of diseasesaffected by or affecting many cell types of the hematopoietic lineageincluding, e.g., autoimmune diseases, heteroimmune conditions ordiseases, inflammatory diseases, cancer (e.g., B-cell proliferativedisorders), and thromboembolic disorders.

In some embodiments, are methods for treating an autoimmune disease orcondition comprising administering to a patient in need a pharmaceuticalformulation of any inhibitor of Btk (or a Btk homolog) of Formula (I) orFormula (II). Such an autoimmune disease or condition includes, but isnot limited to, rheumatoid arthritis, psoriatic arthritis,osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes,myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome,acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, andvulvodynia. In some embodiments, the autoimmune disease is selected fromrheumatoid arthritis or lupus.

In some embodiments, are methods for treating a heteroimmune disease orcondition comprising administering to a patient in need a pharmaceuticalformulation of any inhibitor of Btk (or a Btk homolog) of Formula (I) orFormula (II). Such a heteroimmune condition or disease includes, but isnot limited to graft versus host disease, transplantation, transfusion,anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs,foods, insect poisons, animal hair, animal dander, dust mites, orcockroach calyx), type I hypersensitivity, allergic conjunctivitis,allergic rhinitis, and atopic dermatitis.

In some embodiments, are methods for treating a cancer comprisingadministering to a patient in need a pharmaceutical formulation of anyinhibitor of Btk (or a Btk homolog) of Formula (I) or Formula (II). Sucha cancer, e.g., B-cell proliferative disorders, includes but is notlimited to diffuse large B cell lymphoma, follicular lymphoma, chroniclymphocytic lymphoma, chronic lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenströmmacroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma,plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginalzone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large Bcell lymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In some embodiments, are methods for treating mastocytosis comprisingadministering to a patient in need a pharmaceutical formulation of anyinhibitor of Btk (or a Btk homolog) of Formula (I) or Formula (II).Mastocytosis includes but is not limited to diseases characterized byhyperactive mast cells.

In some embodiments, are methods for treating osteoporosis or boneresorption disorders comprising administering to a patient in need apharmaceutical formulation of any inhibitor of Btk (or a Btk homolog) ofFormula (I) or Formula (II). Bone resorption disorders include but arenot limited to Paget's disease of bone, osteoporosis, and the bonechanges secondary to cancer, such as occur in myeloma and metastasesfrom breast cancer.

In some embodiments, are methods for treating inflammatory diseasescomprising administering to a patient in need a pharmaceuticalformulation of any inhibitor of Btk (or a Btk homolog) of Formula (I) orFormula (II). Inflammatory diseases include but are not limited toasthma, inflammatory bowel disease, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

A subset of tyrosine kinases other than Btk are also expected to beuseful as therapeutic targets in a number of health conditions,including:

-   -   autoimmune diseases, which include, but are not limited to,        rheumatoid arthritis, psoriatic arthritis, osteoarthritis,        Still's disease, juvenile arthritis, lupus, diabetes, myasthenia        gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'        disease Sjögren's syndrome, multiple sclerosis, Guillain-Barré        syndrome, acute disseminated encephalomyelitis, Addison's        disease, opsoclonus-myoclonus syndrome, ankylosing        spondylitisis, antiphospholipid antibody syndrome, aplastic        anemia, autoimmune hepatitis, coeliac disease, Goodpasture's        syndrome, idiopathic thrombocytopenic purpura, optic neuritis,        scleroderma, primary biliary cirrhosis, Reiter's syndrome,        Takayasu's arteritis, temporal arteritis, warm autoimmune        hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia        universalis, Behçet's disease, chronic fatigue, dysautonomia,        endometriosis, interstitial cystitis, neuromyotonia,        scleroderma, and vulvodynia.    -   heteroimmune conditions or diseases, which include, but are not        limited to graft versus host disease, transplantation,        transfusion, anaphylaxis, allergies (e.g., allergies to plant        pollens, latex, drugs, foods, insect poisons, animal hair,        animal dander, dust mites, or cockroach calyx), type I        hypersensitivity, allergic conjunctivitis, allergic rhinitis,        and atopic dermatitis.    -   inflammatory diseases, which include, but are not limited to        asthma, inflammatory bowel disease, appendicitis, blepharitis,        bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,        cholecystitis, colitis, conjunctivitis, cystitis,        dacryoadenitis, dermatitis, dermatomyositis, encephalitis,        endocarditis, endometritis, enteritis, enterocolitis,        epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,        gastroenteritis, hepatitis, hidradenitis suppurativa,        laryngitis, mastitis, meningitis, myelitis myocarditis,        myositis, nephritis, oophoritis, orchitis, osteitis, otitis,        pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,        pleuritis, phlebitis, pneumonitis, pneumonia, proctitis,        prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,        stomatitis, synovitis, tendonitis, tonsillitis, uveitis,        vaginitis, vasculitis, and vulvitis.    -   a cancer, e.g., B-cell proliferative disorders, which include,        but are not limited to diffuse large B cell lymphoma, follicular        lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic        leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic        lymphoma/Waldenström macroglobulinemia, splenic marginal zone        lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal        zone B cell lymphoma, nodal marginal zone B cell lymphoma,        mantle cell lymphoma, mediastinal (thymic) large B cell        lymphoma, intravascular large B cell lymphoma, primary effusion        lymphoma, burkitt lymphoma/leukemia, and lymphomatoid        granulomatosis.    -   thromboembolic disorders, which include, but are not limited to        myocardial infarct, angina pectoris (including unstable angina),        reocclusions or restenoses after angioplasty or aortocoronary        bypass, stroke, transitory ischemia, peripheral arterial        occlusive disorders, pulmonary embolisms, and deep venous        thromboses.    -   mastocytosis, which include but are not limited to diseases        characterized by hyperactive mast cells.    -   bone resorption disorders, which include but are not limited to        Paget's disease of bone, osteoporosis, and the bone changes        secondary to cancer, such as occur in myeloma and metastases        from breast cancer.

Symptoms, diagnostic tests, and prognostic tests for each of theabove-mentioned conditions include, e.g., Harrison's Principles ofInternal Medicine®,” 16th ed., 2004, The McGraw-Hill Companies, Inc. Deyet al. (2006), Cytojournal 3(24), and the “Revised European AmericanLymphoma” (REAL) classification system (see, e.g., the websitemaintained by the National Cancer Institute).

A number of animal models are useful for establishing a range oftherapeutically effective doses of inhibitors, including Btk inhibitorcompounds for treating any of the foregoing diseases. Also, for example,dosing of inhibitor compounds for treating an autoimmune disease can beassessed in a mouse model of rheumatoid arthritis. In this model,arthritis is induced in Balb/c mice by administering anti-collagenantibodies and lipopolysaccharide. See Nandakumar et al. (2003), Am. J.Pathol 163:1827-1837. In another example, dosing of inhibitors for thetreatment of B-cell proliferative disorders can be examined in, e.g., ahuman-to-mouse xenograft model in which human B-cell lymphoma cells(e.g. Ramos cells) are implanted into immunodefficient mice (e.g.,“nude” mice) as described in, e.g., Pagel et al. (2005), Clin Cancer Res11(13):4857-4866. Animal models for treatment of thromboembolicdisorders are also known.

In one embodiment, the therapeutic efficacy of the compound for one ofthe foregoing diseases is optimized during a course of treatment. Forexample, a subject being treated optionally undergoes a diagnosticevaluation to correlate the relief of disease symptoms or pathologies toinhibition of in vivo Btk activity achieved by administering a givendose of a Btk inhibitor. Cellular assays are used to determine in vivoactivity of Btk in the presence or absence of a Btk inhibitor. Forexample, since activated Btk is phosphorylated at tyrosine 223 (Y223)and tyrosine 551 (Y551), phospho-specific immunocytochemical staining ofP-Y223 or P-Y551-positive cells are used to detect or quantifyactivation of Btk in a population of cells (e.g., by FACS analysis ofstained vs unstained cells). See, e.g., Nisitani et al. (1999), Proc.Natl. Acad. Sci, USA 96:2221-2226. Thus, the amount of the Btk inhibitorcompound that is administered to a subject is optionally increased ordecreased as needed so as to maintain a level of Btk inhibition optimalfor treating the subject's disease state.

Combination Treatments

In some embodiments, the Btk inhibitor compositions described herein areused in combination with other well known therapeutic reagents that areselected for their therapeutic value for the condition to be treated. Ingeneral, the compositions described herein and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and are optionally,because of different physical and chemical characteristics, have to beadministered by different routes. The initial administration is made,for example, according to established protocols, and then, based uponthe observed effects, the dosage, modes of administration and times ofadministration are modified.

In certain instances, it is appropriate to administer at least one Btkinhibitor compound described herein in combination with anothertherapeutic agent. By way of example only, if one of the side effectsexperienced by a patient upon receiving one of the Btk inhibitorcompounds described herein is nausea, then it is appropriate toadminister an anti-nausea agent in combination with the initialtherapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein is enhanced byadministration of an adjuvant (i.e., by itself the adjuvant has minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the patient is enhanced). Or, by wayof example only, the benefit experienced by a patient is increased byadministering one of the compounds described herein with anothertherapeutic agent (which also includes a therapeutic regimen) that alsohas therapeutic benefit. In any case, regardless of the disease,disorder or condition being treated, the overall benefit experienced bythe patient is in some embodiments simply additive of the twotherapeutic agents or in other embodiments, the patient experiences asynergistic benefit.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds areoptionally administered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is based on an evaluation of the disease beingtreated and the condition of the patient.

Therapeutically-effective dosages can vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents for use incombination treatment regimens are described in the literature. Forexample, the use of metronomic dosing, i.e., providing more frequent,lower doses in order to minimize toxic side effects, has been describedextensively in the literature Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (I) or Formula (II) described herein) are optionallyadministered in any order or even simultaneously. If simultaneously, themultiple therapeutic agents are optionally provided in a single, unifiedform, or in multiple forms (by way of example only, either as a singlepill or as two separate pills). One of the therapeutic agents may begiven in multiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations arealso envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder from which the subject suffers, as well as the age, weight,sex, diet, and medical condition of the subject. Thus, the dosageregimen actually employed can vary widely and therefore can deviate fromthe dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also are optionally used incombination with procedures that provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

In some embodiments, the compounds described herein and combinationtherapies are administered before, during or after the occurrence of adisease or condition, and the timing of administering the compositioncontaining a compound can vary. Thus, for example, the compounds can beused as a prophylactic and can be administered continuously to subjectswith a propensity to develop conditions or diseases in order to preventthe occurrence of the disease or condition. The compounds andcompositions can be administered to a subject during or as soon aspossible after the onset of the symptoms. The administration of thecompounds can be initiated within the first 48 hours of the onset of thesymptoms, within the first 6 hours of the onset of the symptoms, orwithin 3 hours of the onset of the symptoms. The initial administrationcan be via any route practical, such as, for example, an intravenousinjection, a bolus injection, infusion over 5 minutes to about 5 hours,a pill, a capsule, transdermal patch, buccal delivery, and the like, orcombination thereof. A compound should be administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease, such as, for example, from about 1 month to about 3 months. Thelength of treatment can vary for each subject, and the length can bedetermined using the known criteria. For example, the compound or aformulation containing the compound can be administered for at least 2weeks, between about 1 month to about 5 years, or from about 1 month toabout 3 years.

Therapeutic Agents for Use in Combination with an Inhibitor Compound

In some embodiments, where the subject is suffering from or at risk ofsuffering from an autoimmune disease, an inflammatory disease, or anallergy disease, a Btk inhibitor compound is used in with one or more ofthe following therapeutic agents in any combination: immunosuppressants(e.g., tacrolimus, cyclosporin, rapamicin, methotrexate,cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, orFTY720), glucocorticoids (e.g., prednisone, cortisone acetate,prednisolone, methylprednisolone, dexamethasone, betamethasone,triamcinolone, beclometasone, fludrocortisone acetate,deoxycorticosterone acetate, aldosterone), non-steroidalanti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, orsulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,celecoxib, or rofecoxib), leflunomide, gold thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline,TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab),abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergyvaccines, antihistamines, antileukotrienes, beta-agonists, theophylline,anticholinergics or other selective kinase inhibitors (e.g p38inhibitors, Syk inhibitors, PKC inhibitors).

In yet other embodiments, where the subject is suffering from or at riskof suffering from a B-cell proliferative disorder (e.g., plasma cellmyeloma), the subjected is treated with a Btk inhibitor compound in anycombination with one or more other anti-cancer agents. In someembodiments, one or more of the anti-cancer agents are proapoptoticagents. Examples of anti-cancer agents include, but are not limited to,any of the following: gossyphol, oblimersen sodium, polyphenol E,Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL),5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib, geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,Taxol™, also referred to as “paclitaxel”, which is a well-knownanti-cancer drug which acts by enhancing and stabilizing microtubuleformation, and analogs of Taxol™, such as Taxotere™. Compounds that havethe basic taxane skeleton as a common structure feature, have also beenshown to have the ability to arrest cells in the G2-M phases due tostabilized microtubules and may be useful for treating cancer incombination with the compounds described herein.

Further examples of anti-cancer agents for use in combination with anBtk inhibitor compound include inhibitors of mitogen-activated proteinkinase signaling, e.g., U0126, PD98059, PD184352, PD0325901,ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002;Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

In further embodiments, other anti-cancer agents are employed incombination with an Btk inhibitor compound include doxorubicin,dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine;interleukin Il (including recombinant interleukin II, or rlL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-1a; interferon gamma-1 b; iproplatin;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

In yet other embodiments, other anti-cancer agents are employed incombination with an Btk inhibitor compound include: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyl uracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronicacid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Yet other anticancer agents that can be employed in combination with aBtk inhibitor compound include alkylating agents, antimetabolites,natural products, or hormones, e.g., nitrogen mustards (e.g.,mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne,ete.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with a Btk inhibitorcompound include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha).

Examples of alkylating agents that are employed in combination a Btkinhibitor compound in some embodiments, include, but are not limited to,nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, ete.). Examples of antimetabolitesinclude, but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination with a Btkinhibitor compound include, but are not limited to,adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol (DES), ethinyl estradiol,antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),gonadotropin releasing hormone analog (e.g., leuprolide). Other agentsthat can be used in the methods and compositions described herein forthe treatment or prevention of cancer include platinum coordinationcomplexes (e.g., cisplatin, carboblatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which are used in someembodiments, in combination with a Btk inhibitor compound includewithout limitation marketed drugs and drugs in development.

Where the subject is suffering from or at risk of suffering from athromboembolic disorder (e.g., stroke), the subject, in some embodimentsis treated with a Btk inhibitor compound in any combination with one ormore other anti-thromboembolic agents. Examples of anti-thromboembolicagents include, but are not limited any of the following: thrombolyticagents (e.g., alteplase anistreplase, streptokinase, urokinase, ortissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran(e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux,draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150),factor VIIa inhibitors, ticlopidine, clopidogrel, CS-747 (prasugrel,LY640315), ximelagatran, or BIBR 1048.

Pharmaceutical Composition/Formulation

In a further aspect are provided pharmaceutical compositions, whichinclude a therapeutically effective amount of at least one of any of thecompounds described herein, or a pharmaceutically acceptable salt,pharmaceutically acceptable tautomer, pharmaceutically acceptableprodrug, or pharmaceutically acceptable solvate. In certain embodiments,compositions provided herein further include a pharmaceuticallyacceptable diluent, excipient and/or binder.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein, or pharmaceutically effectivederivatives thereof, that deliver amounts effective for the treatment,prevention, or amelioration of one or more symptoms of diseases,disorders or conditions that are modulated or otherwise affected bytyrosine kinase activity, or in which tyrosine kinase activity isimplicated, are provided. The effective amounts and concentrations areeffective for ameliorating any of the symptoms of any of the diseases,disorders or conditions disclosed herein.

Pharmaceutical compositions are formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Asummary of pharmaceutical compositions described herein is found, forexample, in Remington: The Science and Practice of Pharmacy, NineteenthEd (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999).

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein, such as, for example, compounds of any ofFormula (I) or Formula (II), with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. The pharmaceutical compositionfacilitates administration of the compound to an organism. In practicingthe methods of treatment or use provided herein, therapeuticallyeffective amounts of compounds described herein are administered in apharmaceutical composition to a mammal having a disease, disorder, orcondition to be treated. Preferably, the mammal is a human. Thecompounds, in some embodiments, are used singly or in combination withone or more therapeutic agents as components of mixtures.

The pharmaceutical formulations described herein in some embodiments, isadministered to a subject by multiple administration routes, includingbut not limited to, oral, parenteral (e.g., intravenous, subcutaneous,intramuscular), intranasal, buccal, topical, rectal, or transdermaladministration routes. The pharmaceutical formulations described hereininclude, but are not limited to, aqueous liquid dispersions,self-emulsifying dispersions, solid solutions, liposomal dispersions,aerosols, solid dosage forms, powders, immediate release formulations,controlled release formulations, fast melt formulations, tablets,capsules, pills, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate and controlled release formulations.

Pharmaceutical compositions including a compound described herein areoptionally manufactured in a conventional manner, such as, by way ofexample only, by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

A “carrier” or “carrier materials” includes excipients in pharmaceuticsand is selected on the basis of compatibility with compounds disclosedherein, such as, compounds of Formula (I) or Formula (II), and therelease profile properties of the desired dosage form. Exemplary carriermaterials include, e.g., binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, diluents, and the like. See, e.g.,Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

A “measurable serum concentration” or “measurable plasma concentration”describes the blood serum or blood plasma concentration, typicallymeasured in mg, μg, or ng of therapeutic agent per ml, dl, or l of bloodserum, absorbed into the bloodstream after administration. As usedherein, measurable plasma concentrations are typically measured in ng/mlor μg/ml.

“Pharmacodynamics” refers to the factors which determine the biologicresponse observed relative to the concentration of drug at a site ofaction. “Pharmacokinetics” refers to the factors which determine theattainment and maintenance of the appropriate concentration of drug at asite of action.

“Steady state,” as used herein, is when the amount of drug administeredis equal to the amount of drug eliminated within one dosing intervalresulting in a plateau or constant plasma drug exposure.

Dosage Forms

Moreover, the pharmaceutical compositions described herein, whichinclude a compound of Formula (I) or Formula (II) are, in someembodiments, formulated into any suitable dosage form, including but notlimited to, aqueous oral dispersions, liquids, gels, syrups, elixirs,slurries, suspensions and the like, for oral ingestion by a patient tobe treated, solid oral dosage forms, aerosols, controlled releaseformulations, fast melt formulations, effervescent formulations,lyophilized formulations, tablets, powders, pills, dragees, capsules,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediaterelease and controlled release formulations.

The pharmaceutical solid dosage forms described herein optionallyinclude a compound described herein and one or more pharmaceuticallyacceptable additives such as a compatible carrier, binder, fillingagent, suspending agent, flavoring agent, sweetening agent,disintegrating agent, dispersing agent, surfactant, lubricant, colorant,diluent, solubilizer, moistening agent, plasticizer, stabilizer,penetration enhancer, wetting agent, anti-foaming agent, antioxidant,preservative, or one or more combination thereof. In still otheraspects, using standard coating procedures, such as those described inRemington's Pharmaceutical Sciences, 20th Edition (2000), a film coatingis provided around the formulation of the compound of Formula (I) orFormula (II). In one embodiment, some or all of the particles of thecompound of Formula (I) or Formula (II), are coated. In anotherembodiment, some or all of the particles of the compound of Formula (I)or Formula (II), are microencapsulated. In still another embodiment, theparticles of the compound of Formula (I) or Formula (II), are notmicroencapsulated and are uncoated.

Examples of Methods of Dosing and Treatment Regimens

The compounds described herein, in some embodiments, is used in thepreparation of medicaments for the inhibition of Btk or a homologthereof, or for the treatment of diseases or conditions that benefit, atleast in part, from inhibition of Btk or a homolog thereof. In addition,a method for treating any of the diseases or conditions described hereinin a subject in need of such treatment, involves administration ofpharmaceutical compositions containing at least one compound of any ofFormula (I) or Formula (II), described herein, or a pharmaceuticallyacceptable salt, pharmaceutically acceptable N-oxide, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said subject.

The compositions containing the compound(s) described herein, in otherembodiments, are administered for prophylactic and/or therapeutictreatments. In therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest thesymptoms of the disease or condition. Amounts effective for this usewill depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In some embodiments, the kinase inhibitor is administered to the patienton a regular basis, e.g., three times a day, two times a day, once aday, every other day or every 3 days. In other embodiments, the kinaseinhibitor is administered to the patient on an intermittent basis, e.g.,twice a day followed by once a day followed by three times a day; or thefirst two days of every week; or the first, second and third day of aweek. In some embodiments, intermittent dosing is as effective asregular dosing. In further or alternative embodiments, the kinaseinhibitor is administered only when the patient exhibits a particularsymptom, e.g., the onset of pain, or the onset of a fever, or the onsetof an inflammation, or the onset of a skin disorder.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from about10%-about 100%, including, by way of example only, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, and is determined according to theparticular circumstances surrounding the case, including, e.g., thespecific agent being administered, the route of administration, thecondition being treated, and the subject or host being treated. Ingeneral, however, doses employed for adult human treatment willtypically be in the range of about 0.02-about 5000 mg per day, or fromabout 1-about 1500 mg per day. The desired dose may conveniently bepresented in a single dose or as divided doses administeredsimultaneously (or over a short period of time) or at appropriateintervals, for example as two, three, four or more sub-doses per day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The foregoing ranges are merely suggestive, as the number of variablesin regard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon. Such dosagesmay be altered depending on a number of variables, not limited to theactivity of the compound used, the disease or condition to be treated,the mode of administration, the requirements of the individual subject,the severity of the disease or condition being treated, and the judgmentof the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Kits/Articles of Manufacture

Articles of manufacture including packaging material, a compound orcomposition or pharmaceutically acceptable derivative thereof providedherein, which is effective for inhibiting the activity of tyrosinekinase(s), such as Btk, within the packaging material, and a label thatindicates that the compound or composition, or pharmaceuticallyacceptable salt, pharmaceutically acceptable tautomer, pharmaceuticallyacceptable prodrug, or pharmaceutically acceptable solvate thereof, isused for inhibiting the activity of tyrosine kinase(s), such as Btk, areprovided.

EXAMPLES

The following specific and non-limiting examples are to be construed asmerely illustrative, and do not limit the present disclosure in any waywhatsoever.

Example 1 Synthesis ofN-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenyl)-2,3-dihydroxypropanamide(4)

To a mixture ofN-(3-{5-fluoro-2-[4-(2-methoxy-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-acrylamide3 (0.2 g, 0.47 mmol) and NMM N-oxide (0.2 g, 1.71 mmol) in THF (10 mL)and t-BuOH (10 mL) was added OsO₄ (0.2 g) at 0° C. The resulting mixturewas stirred at room temperature for 24 h and then Na₂S₂O₄ (1 g) wasadded. The mixture was stirred at room temperature for 16 h and thenconcentrated. The residue was subjected to FCC (5% CH₃OH/DCM) to affordthe title compound,N-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenyl)-2,3-dihydroxypropanamide(0.18 g, 83%).

Example 2 Synthesis of(S)-2-amino-5-((R)-1-(carboxymethylamino)-3-(3-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenylamino)-3-oxopropylthio)-1-oxopropan-2-ylamino)-5-oxopentanoicacid (5)

To a suspension ofN-(3-{5-fluoro-2-[4-(2-methoxy-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-acrylamide3 (0.1 g, 0.236 mmol) and glutathione (0.1 g, 0.325 mmol) in DCM (10 mL)and CH₃OH (10 mL) was added TEA (0.1 g, 0.988 mmol) dropwise at 0° C.The resulting mixture was stirred at room temperature for 16 h and thenconcentrated. The residue was washed with H₂O and dried to afford thetitle compound,(S)-2-amino-5-((R)-1-(carboxymethylamino)-3-(3-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenylamino)-3-oxopropylthio)-1-oxopropan-2-ylamino)-5-oxopentanoicacid (0.17 g, 100%).

Example 3 Inhibition of Btk

The Btk IC₅₀s of compounds disclosed herein is determined in enzymatickinase assay as described below.

Kinase activity is measured in vitro using electrophoretic mobilityshift assay. The kinase reactions are assembled in a total volume of 25μL in 384 well plates. The reactions comprise: BTK enzyme (1 nM,N-terminal His6-tagged, recombinant, full-length, human BTK purifiedfrom baculovirus Sf21 insect cell system), inhibitor, ATP (16 μM, theapparent K_(m) for the kinase), fluorescently labeled peptide substrate(1 μM, FAM-GEEPLYWSFPAKKK-NH2) in a reaction buffer composed of 100 mMHEPES, pH7.5, 5 mM MgCl₂ 1 mM DTT, 0.1% bovine serum albumin, 0.01%Triton X-100, and 1% DMSO. The reaction is incubated for one hour and isquenched by the addition of 45 μL of termination buffer (100 mM HEPES,pH7.5, 0.01% Triton X-100, 30 mM EDTA). The terminated reactions areanalyzed using 12 channel LabChip® 3000 microfluidic detectioninstrument (Caliper Life Sciences). The enzymatic phosphorylation of thepeptide results in a change in net charge, enabling electrophoreticseparation of product from substrate peptide. As substrate and productpeptides are separated, two peaks of fluorescence are observed. Changein the relative fluorescence intensity of the substrate and productpeaks is the parameter measured, reflecting enzyme activity. In thepresence of an inhibitor, the ratio between product and substrate isaltered: the signal of the product decreases, while the signal of thesubstrate increases.

Activity in each sample is determined as the product to sum ratio (PSR):P/(S+P), where P is the peak height of the product peptide and S is thepeak height of the substrate peptide. For each compound, enzyme activityis measured at various concentrations (12 concentrations of compoundspaced by 3× dilution intervals). Negative control samples(0%-inhibition in the absence of inhibitor) and positive control samples(100%-inhibition, in the presence of 20 mM EDTA) are assembled inreplicates of four and are used to calculate %-inhibition values foreach inhibitor at each concentration. Percent inhibition (P_(inh)) isdetermined using following equation:

P_(inh)=(PSR_(0%)−PSR_(inh))/(PSR_(0%)−PSR_(100%))*100, where PSR_(inh)is the product sum ratio in the presence of inhibitor, PSR_(0%) is theaverage product sum ration in the absence of inhibitor and PSR_(100%) isthe average product sum ratio in 100%-inhibition control samples;

The IC50 values of inhibitors are determined by 4 parameter sigmoidaldose-response model fitting of the inhibition curves (P_(inh) versusinhibitor concentration) using XLfit 4 software.

Compound BTK IC50 4 <500 nM

The properties of the compounds disclosed herein are furthercharacterized by assaying a number of cellular biochemical andfunctional endpoints to assess the selectivity of these compounds forinhibition of Btk versus the closely related protein kinases Lck, Lyn,and Syk. In anti-IgM-stimulated Ramos cells (a human B cell line), areassayed Btk-dependent phosphorylation of PLC-γ1; Lyn and Syk-dependentphosphorylation of tyrosine 551 on Btk; and BCR-activated calcium flux.The effect of compounds disclosed herein on Jurkat cells are measuredwherein a human T cell line in which Lck and Itk, but not Btk arerequired for T cell receptor mediated Ca²⁺ flux.

Example 4 Use of a Compound of Formula (I) or Formula (II) to TreatRheumatoid Arthritis

The in vivo efficacy of the compounds described herein are evaluated ina mouse model of rheumatoid arthritis. Arthritis is induced in Balb/cmice by administration of anti-collagen antibodies andlipopolysaccharide (LPS). See Nandakumar et al. (2003), Am. J. Pathol.163:1827-1837. Female Balb/c mice are treated with 100 mg/kg of ChemiconmAb cocktail to Type II collagen intravenously on Day 0 and 1.25 mg/kgof LPS intraperitoneally on Day 1. A test compound is administeredorally in a methylcellulose-based aqueous suspension formulation at 1,3, 10 and 30 mg/kg once daily starting on Day 2 through Day 12. Bloodsamples are collected at 0.5 and 2 hours post dose of the test compoundadministration on Day 12. The serum concentrations of the test compoundare quantified by LC/MS/MS. Twenty four hours post dose, levels of thetest compound below the level of quantitation.

Example 5 Inhibition of Mast Cell Degranulation

Human CD34+ cells differentiated to mast cells by 9 weeks in culture inthe presence of 1 ng/ml IL-3, 50 ng/ml IL-6, 100 ng/ml SCF. Cells areincubated with IgE+IL-4 for 4 days and then degranulation is induced bycross-linking with anti-IgE. Degranulation quantitated usinghexosaminidase assay. The IC₅₀ in MC degranulation of the compounds aredetermined. Compounds with desired IC₅₀ values are used for thetreatment of inflammatory diseases, such as asthma.

Example 6 Pharmaceutical Compositions

The compositions described below are presented with a compound ofFormula (I) or Formula (II) for illustrative purposes; any of thecompounds of any of Formula (I) or Formula (II) are optionally used insuch pharmaceutical compositions.

Example 6a Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (I) or Formula (II) is dissolved in DMSO and thenmixed with 10 mL of 0.9% sterile saline. The mixture is incorporatedinto a dosage unit form suitable for administration by injection.

Example 6b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I) or Formula (II) is mixed with 750 mg of starch.The mixture is incorporated into an oral dosage unit for, such as a hardgelatin capsule, which is suitable for oral administration.

Example 6c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (I) or Formula (II),with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup,2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gentlyblended and poured into a mold to form a lozenge suitable for buccaladministration.

Example 6d Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (I) or Formula (II) is mixed with 50 mg ofanhydrous citric acid and 100 mL of 0.9% sodium chloride solution. Themixture is incorporated into an inhalation delivery unit, such as anebulizer, which is suitable for inhalation administration.

Example 6e Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (I) or Formula (II) is mixed with 2.5 g ofmethylcellulose (1500 mPa), 100 mg of methylparaben, 5 g of glycerin and100 mL of purified water. The resulting gel mixture is then incorporatedinto rectal delivery units, such as syringes, which are suitable forrectal administration.

Example 6f Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I) or Formula (II) is mixed with 1.75 g ofhydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropylmyristate and 100 mL of purified alcohol USP. The resulting gel mixtureis then incorporated into containers, such as tubes, which are suitablefor topical administration.

Example 6g Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound of Formula (I) or Formula (II) is mixed with 0.9 g of NaCl in100 mL of purified water and filtered using a 0.2 micron filter. Theresulting isotonic solution is then incorporated into ophthalmicdelivery units, such as eye drop containers, which are suitable forophthalmic administration.

1. A compound having the structure of Formula (I):

wherein: R_(a), R_(b), R_(c), R_(d) and R_(e) are each independentlyselected from H, F, Cl, Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and —CO₂R₃; orR_(a) or R_(b) together with one of R_(c), R_(d) and R_(e) and thecarbon atoms to which they are attached form an epoxide; wherein R_(a),R_(b), R_(c), R_(d), and R_(e) cannot all be H; X is F, Cl, Br, I, orCF₃; Y is F, Cl, Br, or I; or —OC₁-C₂alkyl optionally substituted withhalogen or —OC₁-C₂alkyl; or an optionally substituted C₂-C₅heterocycle;R₂ is selected from H, C₁-C₄alkyl, a cysteine amino acid fragment, and aglutathione fragment; each R₃ is independently selected from H,C₁-C₄alkyl, phenyl, and benzyl; or a pharmaceutically acceptable salt orsolvate thereof.
 2. The compound of claim 1 wherein R_(a) is H.
 3. Thecompound of claim 2 wherein R_(b) is —OR₃.
 4. The compound of claim 3wherein R₃ is H.
 5. The compound of claim 1 wherein at least two ofR_(c), R_(d), and R_(e) are H.
 6. The compound of claim 5 wherein R_(c)and R_(d) are both H.
 7. The compound of claim 6 wherein R_(e) is —OR₃.8. The compound of claim 7 wherein R₃ is H.
 9. The compound of claim 8wherein R_(a) and R_(b) are both H.
 10. The compound of claim 8 whereinR_(a) is H and R_(b) is —OR₃.
 11. The compound of claim 10 wherein R₃ isH.
 12. The compound of claim 5 wherein R_(c), R_(d), and R_(e) are eachindependently H.
 13. The compound of claim 12 wherein R_(a) is H andR_(b) is —OR₃.
 14. The compound of claim 13 wherein R₃ is H.
 15. Thecompound of claim 1 wherein R_(a) or R_(b) together with one of R_(c),R_(d) and R_(e) and the carbon atoms to which they are attached form anepoxide.
 16. A compound having the structure of Formula (II):

wherein: R_(a), R_(b), R_(c), R_(d) and R_(e) are each independentlyselected from H, F, Cl, Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and —CO₂R₃; orR_(a) or R_(b) together with one of R_(c), R_(d) and R_(e) and thecarbon atoms to which they are attached form an epoxide; wherein R_(a),R_(b), R_(c), R_(d), and R_(e) cannot all be H; R₂ is selected from H,C₁-C₄alkyl, a cysteine amino acid fragment, and a glutathione fragment;each R₃ is independently selected from H, C₁-C₄alkyl, phenyl, andbenzyl; or a pharmaceutically acceptable salt or solvate thereof.
 17. Acompound having the structure

or a pharmaceutically acceptable salt or solvate thereof.
 18. Apharmaceutical composition comprising a compound having the structure ofFormula (I):

wherein: R_(a), R_(b), R_(c), R_(d) and R_(e) are each independentlyselected from H, F, Cl, Br, I, —CN, —SR₂, —OR₃, —N(R₃)₂, and —CO₂R₃; orR_(a) or R_(b) together with one of R_(c), R_(d) and R_(e) and thecarbon atoms to which they are attached form an epoxide; wherein R_(a),R_(b), R_(c), R_(d), and R_(e) cannot all be H; X is F, Cl, Br, I, orCF₃; Y is F, Cl, Br, or I; or —OC₁-C₂alkyl optionally substituted withhalogen or —OC₁-C₂alkyl; or an optionally substituted C₂-C₅heterocycle;R₂ is selected from H, C₁-C₄alkyl, a cysteine amino acid fragment, and aglutathione fragment; each R₃ is independently selected from H,C₁-C₄alkyl, phenyl, and benzyl; or a pharmaceutically acceptable salt orsolvate thereof; and a pharmaceutically acceptable excipient, binder orcarrier.
 19. The compound of claim 1 wherein the compound is in anisolated form.